JP3496153B2 - Method for producing active substance-containing fine particles comprising a hydrolyzable polymer - Google Patents

Abstract

PCT No. PCT/DE91/01002 Sec. 371 Date Jun. 22, 1993 Sec. 102(e) Date Jun. 22, 1993 PCT Filed Dec. 18, 1991 PCT Pub. No. WO92/11000 PCT Pub. Date Jul. 9, 1992.The invention concerns a method for the production of microscopic particles made of hydrolytically decomposable polymers, in particular copolymers, and containing active substances, using fluid gas with a uniform particle-size distribution and by the addition of biologically compatible amino acids. The microscopic particles produced by this method can be used as drugs for the treatment of humans or animals.

Description

The present invention relates to a method for producing active substance-containing microparticles composed of a hydrolyzable polymer.

From the description of numerous publications, absorbable polyester,
In particular, those based on lactic acid or glycolic acid, especially their copolymers, are decomposed in human or animal tissues or in human or animal body fluids to give compounds which are completely ecologically distinct, in which case It is known that the decomposition rate of a polymer can be varied over several hours to several months depending on the purpose of use.

Degradation products are obtained by normal biochemical exchanges and are either directly excreted or ultimately metabolized to water and carbon dioxide.

Absorbable polyesters are used to produce storage forms with delayed and sustained release of the active substance in the case of galenical preparation,
Especially useful and important.

However, polyesters of this kind can only be used in human or animal organs if they do not contain contaminants which can possibly trigger irritation. The pollutants are, for example, undegraded residual monomers, molecular weight regulators or polymerization catalysts.

Delayed-pharmaceutical forms made using absorbable polyesters of this kind are suitable for being introduced as subcutaneous injections or implants in the body and to date have been made by the following method: − Microencapsulation method using organic solvent (LMSa
nders et al., J. Contr. Release, 2 (1985) 187 or P.
B. Deasy, Microencapsulation and Related Drug Proce
sses, M. dekker Inc., New York 1984);-emulsion polymerization followed by solvent evaporation (TRTice).
& RMGilley, J. Contr. Release, 2 (1985) 34
3);-Angular mist drying method (DLWise et al., Life Sci., 19 (1976
867; -Extrusion method (AJ Schwope et al., Life Sci., 17 (1975)
1877); − Melt burial method (AJ Schwope et al., Life Sci., 17 (1975)
1877); or-interfacial polymerization (G. Birrenbach & P. Speiser, J. Phar
m.Sci., 65 (1976) 1763); however, in the method described, the delayed medicinal form that results is due to the fact that this method works with large amounts of toxic organic solvents. The disadvantage of having a high residual solvent concentration in form; eg JP Benoit et al., Int. J. Pharmaceut
ics, 29 (1986) 95, or the described method, in particular, has the disadvantage that it is operated at elevated temperatures or pressures which cause a significant local temperature rise and can impair the incorporated drug substance. ; As an example, LM Sanders et al., J. Phar
m.Sci., 75 (1986) 356. Topically toxic tissue reactions with organic solvents should be expected if this type of pharmaceutical form remains subcutaneous or in the tissue for a longer period of time. Therefore, the solvent balance should be removed from the listed products as much as possible.

A detailed description of the manufacturing method which is known in the state of the art can be found in the German patent application DE 37 44 329 A1.

Finally, "Aerosol Solvent Extraktion System"
A method for producing active substance-loaded microparticles designated as (ASES) is known from the description of EP 0322687A2.

When using said method, the active substance-loaded microparticles are produced using a flowing gas. In a supercritical atmosphere,
From the solution of polymer and active substance, fine particles are formed, in which case the solvent is removed by absorption in the gas phase.

Fine particles loaded with the active substance are the smallest amount of organic solvent (10
(less than 1 ppm) and is self-sterilizing without residual monomers, molecular weight regulators or polymerization catalysts, the method is however suitable, however, in the case of increasing batch volume, it remains reliably constant. It is disadvantageous that the particle size distribution of 1 is not achieved and that not all hydrolyzable polymers can be reliably processed into fine particles.

The object of the invention is therefore to produce active substance-loaded microparticles having a uniform particle size distribution from hydrolysable polymers, in particular lactic acid and glycolic acid copolymers.

According to the invention, at least one physiologically tolerable amino acid is added to a solution of a hydrolyzable polymer or copolymer and at least one active substance in a corresponding solvent, in a supercritical atmosphere. At this point fine particles were formed, in which case the solvent was solved by being removed by absorption in the gas phase.

According to the invention, all agents may be used. Examples of agents are pharmaceutical agents, toxins and viruses. Regarding the concept of pharmaceutical agents, US Pat. No. 3,773,919 is pointed out.

All biologically acceptable hydrolyzable polymers and copolymers can be used as support materials.

The following are mentioned by way of example: poly-1-lactide (1-PLA), poly-d, l-lactide (RLA), poly-1-lactide coglycolide (1-PLG).
A) and poly-d, l-lactide coglycolide (PLGA) with different contents of lactic acid (LA) and glycolic acid (GA) monomers. The polymeric lactide coglycolide is preferably in a molar ratio between 85:15 and 50:50, particularly preferably in a molar ratio of 75:25.

Amino acids that can be used according to the invention are, but not limited to, L-lysine, L-phenylalanine, L-tryptophan or D, L-phenianalanine.

According to an embodiment of the invention, nitrogen oxides, carbon dioxide, halogenated hydrocarbons, saturated or unsaturated hydrocarbons, nitrogen dioxide or ammonia or mixtures thereof are used as fluidizing gas.

According to another mode of realization of the invention, the corresponding suitable gas capable of transitioning to the supercritical state and the low-boiling liquids and their mixtures can each be used as flowing gas.

  The following example illustrates the invention in detail.

Example 1 Buserelin-containing fine particle polymer: poly- (D, L) lactide coglycolide, production of 0.8 dl / g by volume L-lysine (Aldrich) 0.375 g
Was dissolved in 25 ml of acetic acid (Merk); poly-
2.5 g of (D, L) lactide coglycolide (monomer ratio 75:25)
Is dissolved in 75 ml of dichloromethane (Merck). Combine the two solutions. Then 0.06 g of buserelin are added and stirred until a clear solution; 0.06% solution, based on buzerelin, results.

The solution is placed in a water storage tank (17) -see Fig. 1, and is supplied using a conduit (50) of a piston pump (16), a conduit (52) and a conduit of a heat exchanger (15). After the reflux of (54), it is supplied to the valve (20) and finally to the nozzle (118) via the conduit (55). A solution containing buserelin and copolymer was sprayed into the distillation column (12) through a conventional one-component nozzle (118), Schlick 121 V type, using an overpressure of 94-96 bar, CO ₂ is 8.9 kg / h in supercritical state and uniform flow rate with 90 bar / 36 ° C
Is passed through the distillation column via the inlet (8). This nozzle has a diameter of 0.5 mm and has a spray angle of 1
It is 0 °.

Corresponding to the high affinity of supercritical CO ₂ for solvents,
The solvent is extracted from the primarily formed droplets; spherical solids remain. CO ₂ loaded with this solvent is
2) and (40) flow out and two magnetic valves (7
And through 9) towards the end of the distillation column and depressurized to 60 bar. This valve is operated to such an extent that the amount of fluid gas flowing into the distillation column per unit time can flow out while maintaining the working pressure of the distillation column.

The CO _{2 which} has been cooled by reducing the pressure to 60 bar and which has been loaded with solvent, is led using a conduit (62) into a separator (10) heated to 21 ° C., where
Solvent mixture, as a result of the significantly reduced soluble in the conditions, separated in CO _2. C liberated from the solvent mixture
O ₂ is again transferred to the supercritical state (90 bar, 36 ° C.) by increasing the pressure and the temperature using the conduits (64 and 32) and is freshly transferred to the distillation column for sufficient drying of the corresponding particles. , Conduit (34), liquid gas pump (4), conduit (36), heat exchanger (5), conduit (38) and through inlet (8).

The removal of the solvent mixture separated in the separator (10) is carried out after the separation of the separator (10) from the circulation through the valves (6) and (13) and the depressurization to body pressure.

After completion of the original spraying time, which is 20 to 50 minutes, further CO ₂ is led by the distillation column until no more solvent can be recovered in the separator (10).

After the end of the drying process, the CO ₂ flow to the distillation column is stopped, the distillation column is depressurized to atmospheric pressure via valves (11) and (14), and the particles are collected at the end of the distillation column (19). Taken out at.

The dry powder withdrawn from the distillation column consists of buserelin-containing spheres with a diameter of 5-10 μm.

Example 2 Fine particle polymer containing H-RH-antagonist: poly-
Production of (D, L) lactide coglycolide, 0.8 dl / g by volume Production is carried out in the same way as in Example 1.

0.375 g L-lysine (Aldrich), 0.06 g LH-RH-antagonist and 2.5 g poly- (D, L) lactide coglycolide [75:25], 0.8 dl / g by volume together with acetic acid (Merck) ) Dissolved in 25 ml and 75 ml of dichloromethane (Merck) and stirred until a clear solution results.

The solution is atomized in the distillation column of a high pressure device using an overpressure of 94-96 bar. In this case, CO ₂ with 90 bar / 36 ° C. at a uniform flow rate is led through the distillation column.
The amount of passing CO ₂ is 8.9 kg / h. As a nozzle, Schlick 121 with a nozzle diameter of 0.5 mm and a spray angle of 10 °
A V-type conventional one-component nozzle is used.

After the end of the original spraying time, CO ₂ is led through the distillation column until the solvent can no longer be recovered in the separator of the high-pressure device.

The dry powder obtained from the distillation column consists of spheres with a diameter of 5-10 μm.

Example 3 Fine-particle polymer containing no active substance: poly- (D, L) lactide coglycolide, production of 0.8 dl / g in volume Production is carried out in the same way as in Example 1.

2.5 g of poly- (D, L) lactide coglycolide [25:25] in 25 ml of acetic acid (each from Merck) containing 75 ml of dichloromethane and 0.375 g of L-lysine (Aldrich),
A solution consisting of 0.8 dl / g by volume is atomized in the distillation column of the high-pressure device using an overpressure of about 94-96 bar. at the same time,
CO ₂ with 90 bar / 36 ° C. in a uniform flow is led through the distillation column. This CO ₂ passage amount is 8.9 kg / h. The nozzle used is a conventional one-component Schlick 121 V nozzle with a nozzle diameter of 0.5 mm and a spray angle of 10 °.

After the end of the original spraying time, CO ₂ is led through the distillation column until the solvent can no longer be recovered in the separator of the high-pressure device.

The following Table 1 summarizes other examples of polymers which can be used for the production of active substance-containing microparticles.

The production of this type of microparticles is carried out in the same manner as detailed in Examples 1-3.

75 ml of each dichloromethane (Merck)
And dissolved in 25 ml acetic acid.

Add each amount of amino acid. D, L-phenylalanine is pre-dissolved in up to 50 ml of ethanol (Merck) in a suitable manner.

The resulting microparticles are sterilized and free of solvent residues, polymerization catalysts or initiator molecules.

  The fine particles have a uniform particle size distribution of 5 to 10 μm.

Therefore, the microparticles may find use as a delayed pharmaceutical form for subcutaneous injection or implantation in the body.

─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Schneider, Hanellore Federal Republic of Germany D-4000 Düsseldorf Ulmenstraße 45 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 9/14 A61K 47 / 30 B01J 13/04 CAPLUS (STN)

Claims (8)

(57) [Claims] 1. A process for the preparation of active substance-loaded preparation microparticles from a polymer hydrolyzable using a flowing gas, a liquid medium containing at least one active substance, at least one as a carrier. Characterized in that a polymer and at least one amino acid are brought into contact with a fluid gas, a liquid medium is removed by the fluid gas, and a preparation, which is liberated from the liquid medium and comprises a carrier carrying an active substance, is obtained in the form of fine particles. And a method for producing finely divided particles of an active substance loaded with a hydrolyzable polymer. 2. A process for producing active substance-loaded preparation fine particles comprising a hydrolyzable polymer using a flowing gas according to claim 1, wherein the polymer is a copolymer. 3. The polymer is poly-1-lactide, poly-d,
Use of a flowing gas according to claim 1 or 2, which is l-lactide or poly-l-lactide coglycolide or poly-d, l-lactide coglycolide with variable content of the respective monomer components. A process for the preparation of active substance-loaded preparation particles which consist of a hydrolyzable polymer. 4. The polymer lactide coglycolide is 85: 15-5.
A process for the preparation of active substance-loaded preparation microparticles of a hydrolyzable polymer using a flowing gas according to any one of claims 1 to 3, which has a molar ratio between 0:50. 5. The active substance load consisting of a hydrolyzable polymer using a flowing gas according to claim 1, wherein the amino acid is L-lysine, L-phenylalanine or L-tryptophan. For producing the prepared finely divided particles. 6. Production of active substance-loaded preparation microparticles of a hydrolyzable polymer using a flowing gas according to claim 1, wherein the amino acid is D, L-phenylalanine. Law. 7. A fluidized gas comprising nitric oxide, carbon dioxide,
Action of a hydrolyzable polymer with a flowing gas according to any one of claims 1 to 6 using halogenated hydrocarbons, saturated or unsaturated hydrocarbons, nitrogen dioxide or ammonia or mixtures thereof. A method for producing substance-loaded preparation fine particles. 8. Use of a fluidizing gas according to any one of claims 1 to 7 in which a suitable gas capable of transitioning to a supercritical state and low boiling point liquids and mixtures thereof are used as fluidizing gas. A process for the preparation of active substance-loaded preparation particles which consist of a hydrolyzable polymer.